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Mao Zhang,
Pariya Sukhumalchandra,
Atim Enyenihi,
Lisa S St John,
Sally A Hunsucker,
Elizabeth A Mittendorf,
Anna Sergeeva,
Kathryn Ruisaard,
Zein Al-Atrache,
Particia A Ropp,
Haroon Jakher,
Tania Rodriguez-Cruz,
Gregory Lizee,
Karen Clise-Dwyer,
Sijie Lu,
Jeffrey J Molldrem,
Gary L Glish,
Paul M Armistead, Gheath Alatrash
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ABSTRACT: PURPOSE: Immunotherapy targeting aberrantly expressed leukemia associated antigens (LAA) has shown promise in the management of acute myeloid leukemia (AML). However, because of the heterogeneity and clonal evolution that is a feature of myeloid leukemia, targeting single peptide epitopes has had limited success, highlighting the need for novel antigen discovery. In this study, we characterize the role of the myeloid azurophil granule protease cathepsin G (CG) as a novel target for AML immunotherapy. EXPERIMENTAL DESIGN: We used Immune Epitope Database and in vitro binding assays to identify immunogenic epitopes derived from CG. Flow cytometry, immunoblotting and confocal microscopy were used to characterize the expression and processing of CG in AML patient samples, leukemia stem cells and normal neutrophils. Cytotoxicity assays determined the susceptibility of AML to CG-specific cytotoxic T lymphocytes (CTL). Dextramer staining and cytokine flow cytometry were performed to characterize the immune response to CG in patients. RESULTS: CG was highly expressed and ubiquitinated in AML blasts, and was localized outside granules in compartments that facilitate antigen presentation. We identified five HLA-A*0201 binding nonameric peptides (CG1-CG5) derived from CG, and demonstrated immunogenicity of the highest HLA-A*0201 binding peptide, CG1. We showed killing of primary AML by CG1-CTL, but not normal bone marrow. Blocking HLA-A*0201 abrogated CG1-CTL mediated cytotoxicity, further confirming HLA-A*0201 dependent killing. Finally, we demonstrated functional CG1-CTLs in peripheral blood from AML patients following allogeneic stem cell transplantation. CONCLUSIONS: CG is aberrantly expressed and processed in AML and is a novel immunotherapeutic target that warrants further development.
Clinical Cancer Research 11/2012; · 7.74 Impact Factor
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Gheath Alatrash,
Elizabeth A Mittendorf,
Anna Sergeeva,
Pariya Sukhumalchandra,
Na Qiao,
Mao Zhang,
Lisa S St John,
Kathryn Ruisaard,
Christine E Haugen,
Zein Al-Atrache, [......],
Yun Wu,
Rebecca S Patenia,
Chantale Bernatchez,
Luis M Vence,
Laszlo G Radvanyi,
Patrick Hwu,
Karen Clise-Dwyer,
Qing Ma,
Sijie Lu,
Jeffrey J Molldrem
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ABSTRACT: PR1 is a HLA-A2-restricted peptide that has been targeted successfully in myeloid leukemia with immunotherapy. PR1 is derived from the neutrophil granule proteases proteinase 3 (P3) and neutrophil elastase (NE), which are both found in the tumor microenvironment. We recently showed that P3 and NE are taken up and cross-presented by normal and leukemia-derived APCs, and that NE is taken up by breast cancer cells. We now extend our findings to show that P3 and NE are taken up and cross-presented by human solid tumors. We further show that PR1 cross-presentation renders human breast cancer and melanoma cells susceptible to killing by PR1-specific CTLs (PR1-CTL) and the anti-PR1/HLA-A2 Ab 8F4. We also show PR1-CTL in peripheral blood from patients with breast cancer and melanoma. Together, our data identify cross-presentation as a novel mechanism through which cells that lack endogenous expression of an Ag become susceptible to therapies that target cross-presented Ags and suggest PR1 as a broadly expressed tumor Ag.
The Journal of Immunology 10/2012; · 5.79 Impact Factor
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Stefan O Ciurea,
Victor Mulanovich,
Rima M Saliba,
Ulas D Bayraktar,
Ying Jiang,
Roland Bassett,
Sa A Wang,
Marina Konopleva,
Marcelo Fernandez-Vina,
Nivia Montes, [......],
Muzaffar Qazilbash,
Simrit Parmar,
Elizabeth Shpall,
Yago Nieto,
Chitra Hosing,
Partow Kebriaei,
Issa Khouri,
Uday Popat,
Marcos de Lima,
Richard E Champlin
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ABSTRACT: Haploidentical stem cell transplantation (SCT) has been generally performed using a T cell depleted (TCD) graft; however, a high rate of nonrelapse mortality (NRM) has been reported, particularly in adult patients. We hypothesized that using a T cell replete (TCR) graft followed by effective posttransplantation immunosuppressive therapy would reduce NRM and improve outcomes. We analyzed 65 consecutive adult patients with hematologic malignancies who received TCR (N = 32) or TCD (N = 33) haploidentical transplants. All patients received a preparative regimen consisting of melphalan, fludarabine, and thiotepa. The TCR group received posttransplantation treatment with cyclophosphamide (Cy), tacrolimus (Tac), and mycophenolate mofetil (MMF). Patients with TCD received antithymocyte globulin followed by infusion of CD34+ selected cells with no posttransplantation immunosuppression. The majority of patients in each group had active disease at the time of transplantation. Outcomes are reported for the TCR and TCD recipients, respectively. Engraftment was achieved in 94% versus 81% (P = NS). NRM at 1 year was 16% versus 42% (P = .02). Actuarial overall survival (OS) and progression-free survival (PFS) rates at 1 year posttransplantation were 64% versus 30% (P = .02) and 50% versus 21% (P = .02). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 20% versus 11% (P = .20), and chronic GVHD (cGVHD) 7% versus 18% (P = .03). Improved reconstitution of T cell subsets and a lower rate of infection were observed in the TCR group. These results indicate that a TCR graft followed by effective control of GVHD posttransplantation may lower NRM and improve survival after haploidentical SCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2012; · 3.15 Impact Factor
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Elizabeth A Mittendorf, Gheath Alatrash,
Na Qiao,
Yun Wu,
Pariya Sukhumalchandra,
Lisa S St John,
Anne V Philips,
Haile Xiao,
Mao Zhang,
Kathryn Ruisaard,
Karen Clise-Dwyer,
Sijie Lu,
Jeffrey J Molldrem
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ABSTRACT: There is little understanding of the impact of tumor-associated neutrophils (TAN) on adaptive immunity to tumors. In this study, we report the results of an investigation of the pathobiologic basis for the prognostic significance of neutrophil elastase, a serine protease found in neutrophil granules, in a model of cyclin E (CCNE)-overexpressing breast cancer. We established that neutrophil elastase was expressed by TAN within breast cancer tissues but not by breast cancer cells. Neutrophil elastase modulated killing of breast cancer cells by CTLs specific for CCNE-derived HLA-A2-restricted peptide (ILLDWLMEV). Breast cancer cells exhibited striking antigen-specific uptake of neutrophil elastase from the microenvironment that was independent of neutrophil elastase enzymatic activity. Furthermore, neutrophil elastase uptake increased expression of low molecular weight forms of CCNE and enhanced susceptibility to peptide-specific CTL lysis, suggesting that CCNE peptides are naturally presented on breast cancer cells. Taken together, our findings reveal a previously unknown mechanism of antitumor adaptive immunity that links cancer cell uptake of an inflammatory mediator to an effective cytolytic response against an important breast cancer antigen.
Cancer Research 05/2012; 72(13):3153-62. · 7.86 Impact Factor
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Gheath Alatrash,
Yoko Ono,
Anna Sergeeva,
Pariya Sukhumalchandra,
Mao Zhang,
Lisa S St John,
Tian-Hui Yang,
Kathryn Ruisaard,
Paul M Armistead,
Elizabeth A Mittendorf,
Hong He,
Na Qiao,
Tania Rodriguez-Cruz,
Shoudan Liang,
Karen Clise-Dwyer,
Eric D Wieder,
Gregory Lizee,
Sijie Lu,
Jeffrey J Molldrem
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ABSTRACT: Cross-presentation is an important mechanism by which exogenous tumor antigens are presented to elicit immunity. Because neutrophil elastase (NE) and proteinase-3 (P3) expression is increased in myeloid leukemia, we investigated whether NE and P3 are cross-presented by dendritic cells (DC) and B cells, and whether the NE and P3 source determines immune outcomes. We show that NE and P3 are elevated in leukemia patient serum and that levels correlate with remission status. We demonstrate cellular uptake of NE and P3 into lysosomes, ubiquitination, and proteasome processing for cross-presentation. Using anti-PR1/human leukocyte antigen-A2 monoclonal antibody, we provide direct evidence that B-cells cross-present soluble and leukemia-associated NE and P3, whereas DCs cross-present only leukemia-associated NE and P3. Cross-presentation occurred at early time points but was not associated with DC or B-cell activation, suggesting that NE and P3 cross-presentation may favor tolerance. Furthermore, we show aberrant subcellular localization of NE and P3 in leukemia blasts to compartments that share common elements of the classic major histocompatibility class I antigen-presenting pathway, which may facilitate cross-presentation. Our data demonstrate distinct mechanisms for cross-presentation of soluble and cell-associated NE and P3, which may be valuable in understanding immunity to PR1 in leukemia.
Journal of immunotherapy (Hagerstown, Md.: 1997) 04/2012; 35(4):309-20. · 3.20 Impact Factor
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ABSTRACT: The variable regions of Ig (idiotype, Id) expressed by malignant B cells can be used as tumor-specific antigens that induce humoral and cellular immunity. However, epitopes derived from Id that stimulate human CD8(+) T-cell immunity are incompletely characterized.
The clonal Ig V(L) of human myeloma cell line U266 and five primary B-cell tumors were sequenced, and peptides corresponding to the Ig V(L) region were tested for their ability to stimulate CTLs from 10 HLA-A*0201-positive normal donors. The CTLs thus generated were tested against peptide-pulsed T2 cells and autologous tumor cells.
Fourteen peptides derived from Ig light chain (V(L)) of U266 and primary B-cell tumors were used to generate 68 CTLs lines that specifically produced IFN-γ when cocultured with peptide-pulsed T2 cells. These CTLs lysed peptide-pulsed T2 cell as well as U266 or autologous tumor targets in an HLA class I-dependent manner. Sequence analysis revealed shared V(L) T-cell epitopes in U266 and primary B-cell tumors, not previously reported within Ig heavy chain (V(H)) sequences.
This study thus identifies novel immunogenic CTLs epitopes from Id V(L), suggests that they are naturally presented on the surface of B-cell malignancies, and supports their inclusion in next-generation Id vaccines. The ability to prime T cells derived from normal HLA-matched donors, rather than patients, may also have direct application to current strategies, designed to generate allogeneic tumor-specific T cells for adoptive transfer.
Clinical Cancer Research 08/2011; 17(18):5945-52. · 7.74 Impact Factor
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ABSTRACT: Advances in the molecular characterization of human tumors have led to increased interest in the development of targeted therapeutics to include cancer vaccines. The recent success of sipuleucel-T, an autologous cellular vaccine administered to patients with hormone-refractory metastatic prostate cancer, suggests that this is a viable therapeutic option in the management of patients with solid tumors. This article focuses on breast cancer vaccines emphasizing delivery platforms, target antigens and novel strategies designed to enhance response to vaccination that are being evaluated in ongoing Phase II clinical trials.
Expert Review of Vaccines 06/2011; 10(6):755-74. · 4.25 Impact Factor
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Gheath Alatrash,
Matteo Pelosini,
Rima M Saliba,
Ebru Koca,
Gabriela Rondon,
Borje S Andersson,
Alexandre Chiattone,
Weiqing Zhang,
Sergio A Giralt,
Amanda M Cernosek,
Partow Kebriaei,
Amin M Alousi,
Uday R Popat,
Chitra Hosing,
Issa F Khouri,
Richard E Champlin,
Marcos J de Lima
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ABSTRACT: Complete remission (CR) is the gold standard for assessing outcomes following chemotherapy for acute myelogenous leukemia (AML). "CRp," a response criterion defined as fulfillment of all criteria for CR except platelet count recovery to ≥100 × 10(9)/L, is associated with inferior outcomes following chemotherapy. The prognostic importance of CRp before allogeneic stem cell transplantation (allo-SCT) remains unknown. We analyzed a cohort of AML (n = 334) and myelodysplastic syndrome (MDS; n = 10) patients to determine the prognostic significance of achieving CR versus CRp before allo-SCT. At time of transplantation, 266 patients were in CR (CR1 and ≥CR2) and 78 in CRp (CR1p and ≥CR2p). Median follow-up was 38 months (3-131 months). Overall survival, progression-free survival, and nonrelapse mortality (NRM) were most favorable in patients transplanted in CR (CR1 or ≥CR2) compared with CRp (CR1p or ≥CR2p). Achieving CR is therefore associated with improved posttransplantation outcomes compared with achieving CRp and is a significant prognostic factor that needs to be considered when evaluating AML/MDS patients for clinical trials and allo-SCT.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2011; 17(12):1841-5. · 3.15 Impact Factor
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ABSTRACT: Immunotherapy for myeloid leukemias remains a cornerstone in the management of this highly aggressive group of malignancies. Allogeneic (allo) stem cell transplantation (SCT), which can be curative in acute and chronic myeloid leukemias, exemplifies the success of immunotherapy for cancer management. However, because of its nonspecific immune response against normal tissue, allo-SCT is associated with high rates of morbidity and mortality, secondary to graft-versus-host disease, which can occur in up to 50% of allo-SCT recipients. Targeted immunotherapy using leukemia vaccines has been heavily investigated, as these vaccines elicit specific immune responses against leukemia cells while sparing normal tissue. Peptide and cellular vaccines have been developed against tumor-specific and leukemia-associated self-antigens. Although not yet considered the standard of care, leukemia vaccines continue to show promising results in the management of the myeloid leukemias.
Expert Review of Hematology 02/2011; 4(1):37-50. · 1.16 Impact Factor
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Gheath Alatrash,
Marcos de Lima,
Nelson Hamerschlak,
Matteo Pelosini,
Xuemei Wang,
Lianchun Xiao,
Fabio Kerbauy,
Alexandre Chiattone,
Gabriela Rondon,
Muzaffar H Qazilbash,
Sergio A Giralt,
Leandro de Padua Silva,
Chitra Hosing,
Partow Kebriaei,
Weiqing Zhang,
Yago Nieto,
Rima M Saliba,
Richard E Champlin,
Borje S Andersson
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ABSTRACT: The optimal pretransplant regimen for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in patients ≥ 55 years of age remains to be determined. The myeloablative reduced-toxicity 4-day regimen i.v. busulfan (Bu) (130 mg/m(2)) and i.v. fludarabine (Flu) (40 mg/m(2)) is associated with low morbidity and mortality. We analyzed 79 patients ≥ 55 years of age (median, 58 years) with AML (n = 63) or MDS (n = 16) treated with i.v. Bu-Flu conditioning regimens between 2001 and 2009 (median follow-up, 24 months). The patients who received this regimen had a good performance status. The 2-year overall survival (OS) rates for patients in first complete remission (CR1), second CR (CR2), or refractory disease and for all patients at time of transplantation were 71%, 44%, 32%, and 46%, respectively; 2-year event-free survival (EFS) rates for patients in CR1, CR2, or refractory disease at time of transplantation and for all patients were 68%, 42%, 30%, and 44%, respectively. One-year transplant-related mortality (TRM) rates for patients who were in CR or who had active disease at the time of transplantation were 19% and 20%, respectively. Grade II-IV acute graft-versus-host (aGVHD) disease was diagnosed in 40% of the patients. Our results suggest that age alone should not be the primary reason for exclusion from receiving myeloablative reduced-toxicity conditioning with i.v. Bu-Flu preceding transplantation in patients with AML/MDS.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2011; 17(10):1490-6. · 3.15 Impact Factor
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Anna Sergeeva, Gheath Alatrash,
Hong He,
Kathryn Ruisaard,
Sijie Lu,
James Wygant,
Bradley W McIntyre,
Qing Ma,
Dan Li,
Lisa St John,
Karen Clise-Dwyer,
Jeffrey J Molldrem
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ABSTRACT: PR1 (VLQELNVTV) is a human leukocyte antigen-A2 (HLA-A2)-restricted leukemia-associated peptide from proteinase 3 (P3) and neutrophil elastase (NE) that is recognized by PR1-specific cytotoxic T lymphocytes that contribute to cytogenetic remission of acute myeloid leukemia (AML). We report a novel T-cell receptor (TCR)-like immunoglobulin G2a (IgG2a) antibody (8F4) with high specific binding affinity (dissociation constant [K(D)] = 9.9nM) for a combined epitope of the PR1/HLA-A2 complex. Flow cytometry and confocal microscopy of 8F4-labeled cells showed significantly higher PR1/HLA-A2 expression on AML blasts compared with normal leukocytes (P = .046). 8F4 mediated complement-dependent cytolysis of AML blasts and Lin(-)CD34(+)CD38(-) leukemia stem cells (LSCs) but not normal leukocytes (P < .005). Although PR1 expression was similar on LSCs and hematopoietic stem cells, 8F4 inhibited AML progenitor cell growth, but not normal colony-forming units from healthy donors (P < .05). This study shows that 8F4, a novel TCR-like antibody, binds to a conformational epitope of the PR1/HLA-A2 complex on the cell surface and mediates specific lysis of AML, including LSCs. Therefore, this antibody warrants further study as a novel approach to targeting leukemia-initiating cells in patients with AML.
Blood 02/2011; 117(16):4262-72. · 9.90 Impact Factor
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Paul M Armistead,
Shoudan Liang,
Hua Li,
Sijie Lu,
Cornelis A M Van Bergen, Gheath Alatrash,
Lisa St John,
Sally A Hunsucker,
Stefanie Sarantopoulos,
J H Frederik Falkenburg,
Jeffrey J Molldrem
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ABSTRACT: Minor histocompatibility antigens (mHA) mediate much of the graft vs. leukemia (GvL) effect and graft vs. host disease (GvHD) in patients who undergo allogeneic stem cell transplantation (SCT). Therapeutic decision making and treatments based upon mHAs will require the evaluation of multiple candidate mHAs and the selection of those with the potential to have the greatest impact on clinical outcomes. We hypothesized that common, immunodominant mHAs, which are presented by HLA-A, B, and C molecules, can mediate clinically significant GvL and/or GvHD, and that these mHAs can be identified through association of genomic data with clinical outcomes.
Because most mHAs result from donor/recipient cSNP disparities, we genotyped 57 myeloid leukemia patients and their donors at 13,917 cSNPs. We correlated the frequency of genetically predicted mHA disparities with clinical evidence of an immune response and then computationally screened all peptides mapping to the highly associated cSNPs for their ability to bind to HLA molecules. As proof-of-concept, we analyzed one predicted antigen, T4A, whose mHA mismatch trended towards improved overall and disease free survival in our cohort. T4A mHA mismatches occurred at the maximum theoretical frequency for any given SCT. T4A-specific CD8+ T lymphocytes (CTLs) were detected in 3 of 4 evaluable post-transplant patients predicted to have a T4A mismatch.
Our method is the first to combine clinical outcomes data with genomics and bioinformatics methods to predict and confirm a mHA. Refinement of this method should enable the discovery of clinically relevant mHAs in the majority of transplant patients and possibly lead to novel immunotherapeutics.
PLoS ONE 01/2011; 6(8):e23217. · 4.09 Impact Factor
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Qing Ma,
Changqing Wang,
Dan Jones,
Kathryn E Quintanilla,
Dan Li,
Yang Wang,
Eric D Wieder,
Karen Clise-Dwyer, Gheath Alatrash,
You Mj,
Mark F Munsell,
Sijie Lu,
Muzaffar H Qazilbash,
Jeffrey J Molldrem
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ABSTRACT: Tumor antigen-specific cytotoxic T lymphocytes (CTL) have been used in the treatment of human cancer, including leukemia. Several studies have established PR1 peptide, an HLA-A2.1-restricted peptide derived from proteinase 3 (P3), as a human leukemia-associated antigen. PR1-specific CTL elicited in vitro from healthy donors have been shown to lyse P3-expressing AML cells from patients. We investigated whether PR1-CTL can be adoptively transferred into NOD/SCID mice to eliminate human leukemia cells.
PR1-CTL were generated in bulk culture from peripheral blood mononuclear cells (PBMC) stimulated with autologous dendritic cells. Human acute myeloid leukemia (AML) patient samples were injected and engrafted in murine bone marrow at 2 weeks post-transfer.
Following adoptive transfer, bone marrow aspirate from mice that received AML alone had 72-88% blasts in a hypercellular marrow, whereas mice that received AML plus PR1-CTL co-infusion had normal hematopoietic elements and only 3-18% blasts in a hypocellular marrow. The PR1-CTL persisted in the bone marrow and liver and maintained a CD45RA⁻CD28+ effector phenotype.
We found that adoptive transfer of PR1-CTL generated in vitro is associated with reduced AML cells in NOD/SCID mice. PR1-CTL can migrate to the sites of disease and maintain their capacity to kill the AML cells. The surface phenotype of PR1-CTL was consistent with their trafficking pattern in both vascular and end-organ tissues.
Cytotherapy 12/2010; 12(8):1056-62. · 3.63 Impact Factor
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Blood 09/2010; 116(11):1824-5. · 9.90 Impact Factor
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British Journal of Haematology 09/2010; 150(6):716-9. · 4.94 Impact Factor
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ABSTRACT: Interferon-alpha (IFN) induces complete cytogenetic remission (CCR) in 20-25% CML patients and in a small minority of patients; CCR persists after IFN is stopped. IFN induces CCR in part by increasing cytotoxic T lymphocytes (CTL) specific for PR1, the HLA-A2-restricted 9-mer peptide from proteinase 3 and neutrophil elastase, but it is unknown how CCR persists after IFN is stopped.
We reasoned that PR1-CTL persist and mediate CML-specific immunity in patients that maintain CCR after IFN withdrawal. We found that PR1-CTL were increased in peripheral blood of 7/7 HLA-A2+ patients during unmaintained CCR from 3 to 88 months after IFN withdrawal, as compared to no detectable PR1-CTL in 2/2 IFN-treated CML patients not in CCR. Unprimed PR1-CTL secreted IFNgamma and were predominantly CD45RA+/-CD28+CCR7+CD57-, consistent with functional naïve and central memory (CM) T cells. Similarly, following stimulation, proliferation occurred predominantly in CM PR1-CTL, consistent with long-term immunity sustained by self-renewing CM T cells. PR1-CTL were functionally anergic in one patient 6 months prior to cytogenetic relapse at 26 months after IFN withdrawal, and in three relapsed patients PR1-CTL were undetectable but re-emerged 3-6 months after starting imatinib.
These data support the hypothesis that IFN elicits CML-specific CM CTL that may contribute to continuous CCR after IFN withdrawal and suggest a role for T cell immune therapy with or without tyrosine kinase inhibitors as a strategy to prolong CR in CML.
PLoS ONE 01/2010; 5(7):e11770. · 4.09 Impact Factor
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Gheath Alatrash,
Maher Albitar,
Susan O'Brien,
Xuemei Wang,
Taghi Manshouri,
Stefan Faderl,
Alessandra Ferrajoli,
Jan Burger,
Guillermo Garcia-Manero,
Hagop M Kantarjian,
Susan Lerner,
Michael J Keating,
William G Wierda
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ABSTRACT: CD52 and CD20 antigens are important therapeutic targets for the monoclonal antibodies (mAbs) alemtuzumab and rituximab respectively. Circulating CD52 (cCD52) and CD20 (cCD20) have prognostic utility in lymphoid malignancies. The efficacy of mAb therapy in patients with chronic lymphocytic leukaemia (CLL) may be adversely affected by cCD52 or cCD20. In this report, blood and bone marrow (BM) cCD52 and cCD20 were measured at response assessment in previously treated (N = 235) patients with CLL who received fludarabine, cyclophosphamide, and rituximab (FCR). Univariate and multivariate statistical models evaluated correlations of pre- and response variables with progression-free (PFS) and overall survival (OS). Response variables included 1996 National Cancer Institute-Working Group (NCI-WG) response, polymerase chain reaction (PCR) for immunoglobulin heavy chain (IGHV) in BM, and cCD52 and cCD20 levels (blood and BM) at response assessment. Using multivariate analysis, response blood and BM cCD52, blood cCD20, and NCI-WG response were significant independent predictors of PFS. At the time of response assessment, BM cCD52 correlated with OS in univariate analysis. cCD52 and cCD20, therefore appear useful in predicting survival and may be important for monitoring patients following salvage FCR (fludarabine, cyclophosphamide, rituximab) therapy. These data further indicate that plasma may be a good target to evaluate for minimal residual disease using cCD52/cCD20 levels.
British Journal of Haematology 11/2009; 148(3):386-93. · 4.94 Impact Factor
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ABSTRACT: The applications of chemotherapy for the treatment of AML have been unchanged over the past three decades, with only 30% of patients demonstrating disease-free survival (DFS) [118]. Despite achieving CR following induction chemotherapy, the majority of patients relapse and succumb to their disease [6]. In view of the limitations encountered by cytarabine/anthracycline based regimes, attention has shifted to immunotherapy as a means to treat AML and provide significant long-term DFS. This chapter will discuss the role of the immune system and recent advances in immunotherapy for the treatment of AML, focusing on cellular and non-cellular approaches.
Cancer treatment and research 01/2009; 145:237-55.
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ABSTRACT: "Foxy methoxy" (chemical name, 5-methoxy-N,N-diisopropyltryptamine) is a hallucinogenic tryptamine that has been abused with increasing frequency since its appearance in the late 1990s. Like other drugs in this class, foxy frequently produces feelings of euphoria, disinhibition, and auditory as well as visual hallucinations. The drug has been linked to adverse effects, including restlessness, agitation, gastrointestinal distress, and muscle tension. In light of the relatively recent advent of foxy as a drug of abuse and given the inability of commercial toxicologic screening tests to detect the presence of hallucinogenic tryptamines, additional adverse effects seem probable. We report ingestion of foxy by a healthy 23-year-old man that resulted in rhabdomyolysis and transient acute renal failure.
Mayo Clinic Proceedings 05/2006; 81(4):550-1. · 5.70 Impact Factor
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Gheath Alatrash,
Thomas E Hutson,
Luis Molto,
Amy Richmond,
Cheryl Nemec,
Tarek Mekhail,
Paul Elson,
Charles Tannenbaum,
Thomas Olencki,
James Finke,
Ronald M Bukowski
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ABSTRACT: Interleukin-12 (IL-12) and interferon alfa-2b (IFN-alpha-2b) are pleiotropic cytokines with activity in renal cell carcinoma (RCC) and malignant melanoma (MM) as single agents. Preclinical studies suggest concurrent administration may have synergistic antitumor effects. We conducted a phase I trial of concurrent subcutaneous (SC) administration of IL-12 and IFN-alpha-2b in patients with metastatic RCC or MM to determine toxicity, maximum-tolerated dose, preliminary efficacy, and effects on chemokine/cytokine gene expression in peripheral blood mononuclear cells (PBMCs).
Cohorts of three to six patients were treated with escalating doses of IL-12 (dose I, 100 ng/kg; dose II, 300 ng/kg; dose III, 500 ng/kg; dose IV, 500 ng/kg SC) given twice weekly and IFN-alpha-2b (dose I, 1.0 MU/m(2); dose II, 1.0 MU/m(2); dose III, 1.0 MU/m(2); dose IV, 3.0 MU/m(2) SC) three times weekly in 4-week cycles. Effects on gene expression were assessed by reverse transcriptase polymerase chain reaction.
Twenty-six patients (19 with RCC, seven with MM) were accrued at dose levels I (n = 3), II (n = 3), III (n = 13), and IV (n = 7). Dose-limiting toxicity included grades 3 and 4 hepatotoxicity and neutropenia/leukopenia. Patients received a median of three cycles of treatment. Two patients with RCC and one patient with MM had partial responses. Median survival was 13.8 months. Reverse transcriptase polymerase chain reaction on PBMCs revealed induction of IP-10, Mig, B7.1 (CD80), interleukin-5, and interferon gamma in selected patients.
Concurrent SC administration of IL-12 and IFN-alpha-2b is possible at the dose levels utilized. Recommended doses for phase II trials are 500 ng/kg IL-12 and 1.0 MU/m(2) IFN-alpha-2b. Consistent induction of IP-10 and Mig, as well as variable induction of B7.1, interleukin-5, and interferon gamma expression was noted in PBMCs.
Journal of Clinical Oncology 08/2004; 22(14):2891-900. · 18.37 Impact Factor
